Bariatric surgery, in particular Roux-en-Y gastric bypass (RYGB) surgery, is currently the only effective therapy for morbid obesity, which is a grave and growing national health problem. The mechanisms through which RYGB increases satiation and reduces eating and body adiposity are poorly understood. It is thought that the major cause of early satiation at meals and reduced overall intake is increased intestinal satiation caused by the entry of ingesta more distally into the small intestine, i.e., into the jejunum, thus leading to increased release of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY). This proposal adapts classical rat models to test RYGB's effects on intestinal satiation, at the levels of both of gut-brain signaling and of brain neural processing. RYGB will be done by one of the co-PIs who performs the technique both experimentally and clinically, assuring a close match between the experimental model and the clinical standard. The experiments include tests of nutrient-specific controls of ingestion that are hypothesized to be affected by RYGB. In addition, both the release patterns and the satiating potency of endogenous GLP-1 and PYY are tested. The brain work builds on progress in the past decade concerning the neural processing of intestinal negative-feedback controls of eating in the caudal brainstem and in the hypothalamus. Finally, because about twice as many women than men suffer from morbid obesity in the USA and because about 85% of patients electing RYGB are women, all the proposed experiments include tests of physiological sex differences, both male-female difference and estrogen-regulated effects in females, the latter especially relevant to understanding and treating the increase in adiposity associated with menopause. Three Specific Aims are proposed: (1) Determine whether the satiating actions of intra-jejunal infusions of Ensure, Intralipid and glucose are increased by RYGB surgery, including the impacts of adipose-tissue loss and of sex differences, i.e., male vs. female and estradiol-treated vs. untreated ovariectomized rats;(2) Determine the effects of RYGB surgery on brain c-Fos expression in response to intra-jejunal infusions of Ensure, glucose and Intralipid, and determine the neurochemical phenotypes of neurons expressing c-Fos, including the impact of sex differences, i.e., male vs. female and estradiol-treated vs. untreated ovariectomized rats and (3) Determine the effects of RYGB on neural signaling mechanisms underlying the satiating actions of intra-jejunal infusions of Ensure, Intralipid and glucose in male vs. female and in estradiol-treated vs. untreated ovariectomized rats. State-of-the-art behavioral, physiological and molecular techniques are used. Thus, the work (1) should help inform behavioral and nutritional counseling for RYGB patients, (2) may suggest strategies for improvement in the RYGB technique, and (3) should provide rational bases for the development pharmaceutical tools to augment or replace RYGB, which is especially desirable for patients who do not desire bariatric surgery or for whom it is not recommended. PUBLIC HEALTH RELEVANCE: Bariatric surgery, in particular Roux-en-Y gastric bypass (RYGB) surgery, is currently the only effective therapy for morbid obesity, which is a grave and growing national health problem. The mechanisms through which RYGB increases satiation and reduces eating and body adiposity are poorly understood. It is thought that increased intestinal satiation caused by the entry of ingesta more distally into the small intestine, leading to increased release of the gut hormones GLP-1 and PYY, is the major cause of early satiation at meals and reduced overall intake. This proposal builds on classical rat models to test RYGB's effects on intestinal satiation, at the levels both of gut-brain signaling and of brain neural processing. In addition, as >80% of RYGB patients are women, the application includes experiments to assess whether sex differences in the physiology of intestinal satiation affect RYGB outcome. This work should lead to new insights that may help improve how bariatric surgery is done and may suggest targets for pharmaceutical alternatives to bariatric surgery in patients for whom is it not desired or appropriate.